Abstract: Lung health is critically dependent on the maintenance of near sterile airways, a process involving mucus production, airway antimicrobial factors, and mucociliary clearance. The contribution of the goblet cell, a specialized airway cell, to this first line of lung defense s largely unknown. Furthermore, the most common pulmonary disorders, and those associated with the highest morbidity and mortality, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) have, as key and overlapping features, increased goblet cells and mucus hypersecretion. For these reasons, the current paradigm for disease pathogenesis suggests that inhibiting mucus hypersecretion will have beneficial and therapeutic effects in these diseases - despite lack of strong evidence to support this approach in human studies or disease models. An alternative paradigm is that goblet cells and mucus are beneficial and that targeting mucus hypersecretion will have no therapeutic benefit, and may in fact be a harmful strategy. In this high risk, yet potentially paradigm shifting proposal we address this relatively simple idea. The objective of this proposal is to understand the role of goblet cells an mucus in maintenance of the normal lung and in response to airway insults and during disease. The central hypothesis is that goblet cells and mucus are required for airway defense and that lack of goblet cells and mucus will worsen, not improve, airway disease outcomes. In these studies, we will broadly ask three questions: First, are goblet cells and mucus required for maintaining normal lungs? Second, are goblet cells and mucus important for responding to airway insults? Third, are goblet cell metaplasia/hyperplasia and mucus hypersecretion beneficial in diseased lungs? Most airway studies, to date, have been performed in murine models limiting their applicability to humans due to important differences between the murine and human lung and lack of murine airway disease models that closely mimic human disease phenotypes. Since porcine and human airway/lung biology are very similar we will perform our studies in pigs. We will investigate goblet cell and mucus biology by conditionally targeting airway goblet cells with the herpes virus type 1 thymidine kinase system in wild-type and CF pigs. This research proposal is well-suited to the New Innovator Award program because it challenges a current paradigm, utilizes a porcine animal model that closely mimics human airway biology, and uses the CF pig model which represents the first non-murine animal model in which a gene responsible for a human disease has been disrupted. These studies have significant public health relevance because findings should lead to novel mechanistic insights and therapeutic development thereby having a high potential impact on many human airway diseases including asthma, COPD, and CF which affect nearly 50 million Americans and are associated with over 45 billion dollars in annual healthcare costs. Public Health Relevance: This highly innovative and potentially paradigm shifting research is important for public health because understanding the roles of goblet cells and mucus will have a critical impact on developing new therapeutic interventions for airway diseases such as COPD, CF, and asthma. Furthermore, the proposed research is germane to NIH's mission focusing on discoveries related to disease pathogenesis and translation of these studies to clinical medicine.